Alzheimer’s Clue Found

This week in the journal Nature, researchers report a step forward in understanding the pathology of Alzheimer’s disease. Two 1) ___ that are commonly mutated in the early-onset form of Alzheimer’s may cause the disorder by altering how presynaptic neurons release neurotransmitters. The mechanism may apply to other neurodegenerative disorders as well. More than 100 different mutations in two genes coding for the proteins presenilin 1 and 2 are associated with early-onset Alzheimer’s disease, but the exact effects of these 2) ___ on neural function is still unclear. This is the first study suggesting that presenilins play a presynaptic role. In 2007, when knockout mice were created that lacked both presenilin genes, the mice ended up with both memory deficits and neurodegeneration in the 3) ___ which are two key features of Alzheimer’s disease. In the current study, an attempt was made to determine on which side of the synapse the presenilins exert their effect. This was done by creating two strains of knockouts: one that lacked both presinilin genes only in the presynaptic neurons of a synapse in the hippocampus – a brain region that plays an important role in 4) ___ – and another where the genes were knocked out just post-synaptically. Measuring neural activity in dissected brain sections, the researchers were able to compare the effects of presenilins on pre- and post-synatpic activity. In presynaptic presenilin knockout mice, the researchers found drastically reduced long-term potentiation (LTP) – a physiological measure of memory formation. In postsynaptic presenilin knockouts, however, LTP was normal. Knocking out presynaptic 5) ___ also altered other aspects of neuronal function and reduced the probability of neurotransmitter release which depends on increases in calcium levels within the 6) ___. By blocking the release of calcium from the endoplasmic reticulum – an intracellular source of calcium – the researchers mimicked the effects of the presynaptic presenilin knockouts in control mice. This result points to intracellular calcium release as a possible mechanism by which presenilins regulate neuronal function. The main take home message is that there is a difference in the way neurons process 7) ___ levels in absence of presenilins, and that has an effect on synaptic function. Researchers studying neurodegenerative diseases have long debated whether knocking out these genes is a good model for 8) ___ because the exact role of the many presenilin mutations associated with the disease is unclear. Some argue that these mutations result in a “loss of function, in which case a knockout model would appropriately represent the changes that occur in Alzheimer’s patients. Others argue that these mutations result in a “gain of function,” or a change that cannot be replicated by knocking out the genes entirely. If patients with Alzheimer’s disease do indeed have non-functioning presenilin genes, the results of this study may suggest that presynaptic neurotransmitter release is a more general mechanism of 9) ___ diseases. For example, Shen and her colleagues found a presynaptic effect in a mouse model of Parkinson’s disease. These changes “might be a precursor to neurodegeneration,” and might therefore provide new targets for disease 10) ___.

ANSWERS: 1) genes; 2) mutations; 3) brain; 4) memory; 5) presenilins; 6) neuron; 7) calcium; 8) Alzheimer’s; 9) neurodegenerative; 10) therapies


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